The element iodine was
discovered in 18111 and recognized as an essential element a
century later in the early 1920s.2, 3 The
recommended daily allowance (RDA) of elemental iodine by the Food and
Nutrition Board of the United States National Academy
of Sciences was not established until 1980, and it was not confirmed
until 1989.1 The World Health Organization made its own
recommendations on iodine intake in 1996, taking into consideration age
and physiological conditions.5 However, the US RDA and
WHO recommendations were not based on whole-body sufficiency for
iodine, but on the minimum amounts of iodine required to
prevent goiter and cretinism.4, 5 In 1930, Thompson, et
al6 stated, "The normal daily requirement of the body
for iodine has never
been determined." This statement is still true today, more than 70
years later. We still don't know the iodine/iodide requirements for
whole-body sufficiency.

Based on an iodine loading
test developed by the author to assess whole body sufficiency for
iodine,7 100-400 times the US RDA
(orthoiodosupplementation) is required to achieve whole-body
sufficiency for iodine. The human adult body retains approximately
1.5 gm of iodine when iodine sufficiency is achieved,8 an
amount 100 times higher than reported in medical textbooks for the
normal adult.5 The amount of iodine present in the thyroid gland in an
iodine-sufficient adult represents only 3.3% of the total body
iodine,8 not the 70-80% reported in medical textbooks.5

Several clinicians are now
using the iodine loading test and implementing orthoiodosupplementation
in their practices. They report a
very good correlation between the results of the loading test and
clinical response of their patients to iodine supplementation (for an
example, see reference 9). As part of a project to study the metabolism
of ingested Lugol solution in tablet form (Iodoral®),
serum
inorganic iodide levels following ingestion of Iodoral® were
measured in two groups of normal volunteers evaluated with serial
blood samples. The results obtained from this study are reported here.
A double peak of serum inorganic iodide levels was observed
in some subjects with a time interval of eight hours between the peaks.
This double peak is typical of substances undergoing an
enterohepatic circulation. This metabolic aspect of ingested inorganic
iodine/iodide has not been previously reported.

The procedure used to measure
urinary iodide levels10 was modified to measure serum inorganic iodide
levels. The detection
method by ion-selective electrode is the same as previously described.10
But the chromatographic purification of iodide from the
other halides by solid state partition on anion exchange resins was
modified. First, instead of 500 mg column with a 10 ml reservoir
(Alltech #309750), the 600 mg syringe cartridge was used (Alltech
#21907). Both chromatographic systems contain the same strong
anion exchanger SAX resin.10 Second, the vacuum manifold
connected to a vacuum pump previously used,10 was replaced
with
Positive Displacement Manifolds (PDM-40, and PDM-20) capable of running
40 and 20 samples, respectively, in the same batch.
The Positive Displacement Manifolds were designed by the author and
built by a precision machining facility. Third, the elution of
the halides was performed with increasing ionic strengths of sodium
nitrate. Because the two chromatographic systems behaved
differently regarding the sequence of elution of the halides, pilot
studies were performed with standard materials of the halides to
optimize the system. In the 500 mg column, fluoride was eluted with the
biological fluid, while with the 600 mg cartridge, chloride
came first with the eluted sample. The sequence of the elution
procedure used for the cartridges is displayed in Figure 1. This
elution sequence resulted in an excellent separation of the halides
with less than 5% overlap. The sensitivity of the assay was 0.006
mg/L if a sample of 10 ml of serum was used. With a smaller volume of
serum, the sensitivity decreased proportionally. All serum
samples measured so far, prior to iodine supplementation, were below
the sensitivity of the assay.

Following informed consent,
two groups of normal subjects were studied. Group I consisted of three
normal women and two normal
men with normal body weight. Subjects in Group I received an amount of
three tablets of Iodoral® (37.5 mg total iodine) orally.
Iodoral® is the tablet form of Lugol solution containing
12.5 mg elemental iodine per tablet.11 Blood samples were obtained at
time
zero, 30 min, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs, and 24 hrs, (eight
samples) following the ingestion of the preparation.

Group II consisted of six
normal women with normal body weight. This group was studied twice:
Before and after 1 month of iodine
supplementation at 50 mg elemental iodine/day (four tablets Iodoral®).
For the loading test, four tablets (50 mg) were ingested and
blood samples were obtained at time zero, 10 min, 20 min, 30 min, 1 hr,
2 hrs, 3 hrs, 4 hrs, 8 hrs, and 24 hrs (10 samples). Serum
samples obtained, following further processing, were frozen in plastic
containers until assayed.

The serum levels of inorganic
iodide in Group I subjects receiving three tablets of Iodoral® are
compared with the levels obtained
pre-supplementation in Group II subjects who ingested four tablets
(Figure 2). At time zero, the serum iodide levels were
undetectable in both groups. Since 10 ml of serum was used in Group I
and 3 ml in Group II, the sensitivity of the assay was 0.006
mg/L for Group I and 0.02 mg/L for Group II.

The serum levels obtained at
10 and 20 minutes in Group II were omitted from this figure for ease of
comparisons since these two
samples were not available in Group I. Also, Group I subjects did not
have a three-hour blood sample, and Group II subjects did not
have a six-hour blood sample. By 30 minutes post ingestion of three
tablets (Group I) and four tablets (Group II), mean serum
iodide levels were 0.4 mg/L and 0.7 mg/L respectively for Group I and
Group II. Peak levels were achieved in both groups between
two and four hours. Serum inorganic iodide levels were still detectable
at 24 hours with 0.4 mg/L and 0.45 mg/L. The mean peak
levels for Group I were around 1.5 mg/L; whereas, for Group II, the
mean peak levels were between 1.8 mg/L and 2.2 mg/L. After
one month of supplementation at 50 mg/day in Group II, four of six
subjects reached peak levels at 10 minutes. These levels were
maintained for 2-3 hours, forming a plateau, followed by a sharp drop,
and a second peak at eight hours post ingestion.

The data on one of the
subjects pre- and post-supplementation are displayed in Figure 3. Prior
to supplementation, the iodide levels
were below 0.02 mg/L at 10 minutes, became measurable at 20 minutes
(0.2 mg/L), increased progressively to reach a peak 1.8
mg/L at two hours, and decreased afterward to levels of 0.4 mg/L at
eight and 24 hours. Following one month of supplementation
with four tablets of Iodoral® (50 mg), the peak levels
were three times higher and shifted to the left by two hours. A plateau
was
maintained between 10 minutes and three hours with levels fluctuating
between 4.6 mg/L and 5 mg/L. At four hours, the serum
iodide level dropped sharply to 1.4 mg/L. No blood samples were
obtained at six hours. A second peak of 3.2 mg/L was observed at
eight hours, suggesting an enterohepatic circulation of iodine.
Following one month of supplementation, steady state conditions
were achieved in this subject, and the serum iodide levels were 1.3
mg/L pre-loading and 1.2 mg/L 24 hours post-loading. As
previously discussed,8 at a daily intake of 50 mg iodine,
expected serum levels at steady state would be equal to 50 mg/day
divided
by 43.5 L/day which computes to 1.15 mg/L. The renal clearance rate of
iodide is 43.5 L/day.8

The second peak of serum
iodide levels eight hours after the first peak, following
supplementation with 50 mg iodine for one month,
was confirmed in a female subject who collected urine samples
individually without pooling for 24 hours following the loading test
with 50 mg (four tablets). This subject excreted 42% of the oral amount
of 50 mg. A total of eight samples of voided urine were
collected over the 24-hour period (Figure 4). The values shown on
Figure 4 are expressed as percentage of the total iodide excreted
in 24 hours, recovered in the voided sample expressed per hour,
therefore representing excretion rate. This value was computed by
dividing the amount of iodide measured in the sample by the interval of
time in hours between collections. For example, if 20% of
the total iodide excreted was recovered in a sample with a time
interval of two hours from the previous void sample, the excretion
rate would be 10%/hr. The first peak of urine iodide excretion rate
occurred in sample #2, collected at five hours post ingestion,
representing a three-hour period (time interval 2-5 hours from
ingestion of iodine). This peak at 2-5 hours coincides with the serum
data with peaks observed between two and four hours post-iodine
administration. Serum iodide is efficiently cleared by the kidneys.
A second peak was observed in sample #6, obtained at 13 hours post
ingestion with a 2-hour interval (11-13 hrs). The interval of
time between the two peaks is approximately eight hours, confirming the
peak observed at eight hours in serum samples when the
first peak was at 10 minutes.

The effect of
orthoiodosupplementation on the profile and levels of serum iodide
following a loading test is suggestive of an effect
of iodine on the efficiency and rapidity of absorption of iodine.
Possibly, this effect of iodine supplementation on iodine absorption
may be applicable to the absorption of other nutrients.

The second peak of serum
iodide following the loading test was not observed in the subjects
prior to iodine supplementation (Figure
2) because such a peak would be expected eight hours after the first
peak. Since the first peaks occurred 2-4 hours after ingestion of
iodine in Figure 2, the second peak would have occurred at 10-12 hours
after the iodine load. No blood sample was obtained
between eight and 24 hrs in those subjects.

An enterohepatic circulation
of ingested inorganic iodine has not been previously reported. Such a
metabolic pathway of iodine
could result in elevated hepatic concentrations of iodine. We
previously reported a significant effect of orthoiodosupplementation on
serum liver enzymes.11 What role iodine plays on liver
functions and bile formation is, at the present, unknown. Some patients
have
reported improved digestion, even with fatty meals, and regular bowel
movement following orthoiodosupplementation. It is possible
that iodine improves the flow of bile from the liver to the
gastrointestinal tract. Iodine deserves more attention from medical
researchers and clinicians.

A careful review of published
data on amiodarone suggests that this organic iodine-containing drug is
a sustained release form of
iodine. The iodine released is the active agent, with the drug itself
being the cause of its toxicity.12 If this is the case,
inorganic
non-radioactive iodine would be the treatment of choice in those
clinical conditions currently treated with amiodarone. In their 2001
publication, Martino et al13 reported a list of
side effects and complications of amiodarone: corneal microdeposits in
100% of the
cases; anorexia, nausea in 80%; skin photosensitivity and discoloration
in 55-75%; neurological symptoms in 48%; abnormal liver
tests in 25%; thyroid dysfunction in 14-18%; and lung dysfunction in
10-13%. The pulmonary toxicity is the most serious
complication of amiodarone therapy, with a fatal outcome in 9% of the
patients experiencing this side effect of amiodarone.14

It is hard to believe that
such a drug is widely used by US physicians in medical conditions where
inorganic non-radioactive iodine
has never been tested. Connolly,15 in his 1999 review of
amiodarone efficacy and safety, reported, "On the basis of the number
of
prescriptions filled in retail pharmacies, amiodarone was the most
often prescribed antiarrhythmic agent, accounting for 24.1% of
the total antiarrhythmic prescriptions in 1998." He further commented
that amiodarone accounted for 33-74% of prescriptions in
Europe and North and South America, compared to 0.3% in Japan, which is
100 times less than the other countries mentioned. It is
of interest that mainland Japanese consume at least 100 times the RDA
for iodine.16, 17 That is at least 100 times more iodine
than
countries with 100 times more prescriptions for amiodarone. Regarding
the evidence-based analysis of amiodarone efficacy and
safety, Connolly stated, "The general view that amiodarone is the most
useful drug for VT and VF, notwithstanding the rather
modest evidence from randomized trials, led to its being adopted as the
standard medical therapy in several recent randomized
secondary prevention trials evaluating the ICD… A meta-analysis of
these trials based on individual patient data yielded a relative
risk reduction in all-case mortality of 13% to 15%, which was of
borderline statistical significance (P=0.03 or 0.06 depending on
analytical method used)."

To make matters worse with
amiodarone, thyroidologists have become so destructive that some of
them recommend radioiodine
ablation of the thyroid to allow the reintroduction of amiodarone
treatment in patients with a prior history of amiodarone-induced
thyrotoxicosis.18 To quote Hermida, et al,18
"However, hypothyroidism should be viewed as a goal, rather than a
complication, of
treatment in these patients." They have gone berserk!

Implementation of
orthoiodosupplementation in the above cases would be appropriate, not
as a treatment for cardiac arrhythmias,
but as a means of supplying these patients with adequate amounts of an
essential nutrient for whole body sufficiency. Who knows?
Orthoiodosupplementation and whole body iodine sufficiency may be the
answer to several clinical conditions currently treated with
toxic drugs.

An enterohepatic circulation
of amiodarone has been reported by Andreasen, et al.19
Since we have observed an enterohepatic
circulation for inorganic iodine, could the iodine present in
amiodarone and released from amiodarone play a role in this
enterohepatic circulation? Broekhuysen, et al,20 using
balance studies of amiodarone and the iodine released from amiodarone,
reported the following. In two subjects treated with 300 mg of
amiodarone/day, the total amount of iodine measured in urine and
feces was very low during the first three days, with a mean of 19% and
7% of the total iodine ingested suggesting that 80-90% of
the iodine ingested was retained in the body. After 25-27 days of
therapy with 300 mg/day, the mean percentage excretion of
combined urine plus feces in these two subjects increased 48% and 75%.
Therefore, after approximately one month, the percentage
of iodine retained by the body had decreased to 25% and 50%. No
inorganic iodine/iodide was found in feces, only the organic
form, amiodarone; whereas, in urine, inorganic iodide was excreted.

In two other subjects treated
with 300 mg/day for seven weeks, balance studies revealed at the end of
the study that the total
excreted iodine in urine and feces averaged 97.4% and 96.9%. The
authors commented, "These results suggest that iodine is
retained in the body until a mechanism is triggered that adjusts the
excretion of iodine to balance completely the intake." They
estimated that the body retained 1.5-2.0 g of iodine before the
ingested iodine in amiodarone is completely excreted, and before
therapeutic efficacy.

In three patients who died
following long-term treatment with amiodarone, the levels of inorganic
iodine present in various organs
and tissues were measured. The total body iodine content was estimated
at approximately 2 g with the greatest amount found in fat
tissues (700 mg) and striated muscle (650 mg). Iodine was present in
every tissue examined. The highest concentrations of iodine
were found in descending order in the thyroid gland, liver, lung, fat
tissues, adrenal glands, and the heart.

When a tablet form of Lugol
solution (Iodoral®) is ingested at a daily amount of 50
mg elemental iodine, whole body sufficiency is
achieved in approximately three months; and the estimated amount of
iodine retained in the body is approximately 1.5 g.8 This is
the
same amount of iodine retained in patients on amiodarone following 4-7
weeks at 300 mg/day. Clinical response to amiodarone is
observed after the same period of time (4-7 weeks) on amiodarone
therapy. These data are suggestive of an important role of
inorganic iodine released from amiodarone in the therapeutic effect of
this drug; and that whole body sufficiency for iodine is a
requirement for optimal cardiac function. If amiodarone is a toxic form
of sustained release iodine, and inorganic iodine is the active
ingredient, why not give inorganic iodine to these unfortunate
patients, saving them from the toxicity of the amiodarone molecule?12

Inorganic non-radioactive
iodine/iodide is an essential nutrient, not a drug. Therefore, the body
has the metabolic mechanism for
using inorganic iodine beneficially, effectively and safely. Iodine is
the safest essential nutrient, with a track record of 180 years of
use in medicine.7 Published data confirms its safety even
when used in pulmonary patients in amounts four orders of magnitude
greater than the US RDA.8

About
the Author

Guy E. Abraham, MD, is a
former Professor of Obstetrics, Gynecology and Endocrinology at the
UCLA School of Medicine. Some
35 years ago, he pioneered the development of assays to measure minute
quantities of steroid hormones in biological fluids. He has
been honored as follows: General Diagnostic Award from the Canadian
Association of Clinical Chemists, 1974; the "Medaille
d'Honneur" from the University of Liege, Belgium, 1976; the Senior
Investigator Award of Pharmacia, Sweden, 1980.

The applications of Dr.
Abraham's techniques to a variety of female disorders have brought a
notable improvement to the
understanding and management of these disorders. Twenty-five years ago,
Dr. Abraham developed nutritional programs for women
with premenstrual tension syndrome and post menopausal osteoporosis.
They are now the most commonly used dietary programs
by American obstetricians and gynecologists. Dr. Abraham's current
research interests include the development of assays for the
measurement of iodide and the other halites in biological fluids and
their applications to the implementation of
orthoiodosupplementation in medical practice.